Summary Exogenous insulin treatment is the standard of care for Type 1 diabetes (T1D), which negatively affects the quality of life and is also often ineffective in preventing recurrent hyperglycemia episodes and its chronic complications. Recent studies show that human islet allografts can restore normoglycemia and insulin independence long-term, protect from severe hypoglycemia, and slow progression of microvascular lesions in immunosuppressed type 1 diabetic recipients. However, there are at least 3 critical barriers to the progress in the field of clinical islet transplantation; i) a limited supply of donor islets, ii) transplantation into the liver, which compromises immediate post-graft islet engraftment as well as long-term survival, and iii) immune rejection, precipitated by both innate and adaptive immune responses, despite chronic use of immunosuppression with the associated various short- and long-term complications. This proposal investigates microporous polymer scaffolds as a platform for the transplantation of human pluripotent stem cell (hPSC) derived immature beta cells into an extrahepatic and clinically translational site. The scaffolds will be modified to positionally display on their surface two recombinant immunological ligands for the signal regulatory protein alpha (SIRPa) and Fas receptor with demonstrated function for the modulation of innate, adaptive, and regulatory immune responses. Our central hypothesis is that the immobilized SIRPa and Fas receptor ligands will block both innate and adaptive immune responses, respectively, while initiating a regulatory circuit locally within the graft that will enhance immature beta cell maturation and achieve sustained graft survival and function in the absence of chronic immunosuppression. The overall objective will be accomplished by testing our central hypothesis through two Specific Aims. Studies under Aim 1 will engineer PLG scaffolds with the immunologic ligands, load the engineered scaffolds with hPSC-derived beta cells, and assess the efficacy of this platform to block innate immune responses and enhance beta cells maturation and engraftment in vivo in an animal model with a restricted adaptive and competent innate immune system. Aim 2 will investigate in a humanized mouse model competent for both innate and adaptive immune responses the efficacy of immunologic ligands- engineered scaffolds to support sustained survival and function of beta cells transplanted into epididymal fat pad, the equivalent of the great omentum in humans, as a clinically relevant site in the absence of chronic immunosuppression. We are well prepared to undertake the proposed research because of the combined expertise of our teams in biomaterial engineering, immunology, and hPSC-derived beta cells. If successful, this approach will overcome the three aforementioned major barriers for wide-spread use of beta cells as a cure for the treatment of type 1 diabetes.